This study will investigate the use of repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation method, to improve word-finding abilities in Veterans and non-Veterans with chronic language problems following stroke (aphasia). Improving word-finding is important because word-finding difficulties are among the most common and debilitating consequences of aphasia. Although rTMS has shown promise as a treatment approach, not all individuals with aphasia show the same level of benefit. Specifically, this study will use functional magnetic resonance imaging (fMRI) to examine whether the likelihood of improved word-finding abilities following rTMS depends on pre-intervention language-related brain activity and will examine changes in brain activity in response to stimulation. A better understanding of how and for whom rTMS works will 1) help to identify the best candidates for rTMS treatment, 2) optimize rTMS treatment protocols to improve patient outcomes, and 3) improve the investigators' understanding of how the brain re-organizes language functions following stroke.

Aphasia, an acquired communication disorder, is a common consequence of left-hemisphere stroke. Persisting, or chronic, aphasia negatively impacts not only interpersonal communication but participation in activities of daily living, independence, and autonomy. It is also associated with higher rates of depression and lower quality of life. Therefore, examining factors and treatments that result in the best possible recovery of language function for individuals with chronic aphasia is of paramount importance.

An intervention approach that has shown promise in early-phase research on treatment of chronic aphasia is repetitive transcranial magnetic stimulation (rTMS). rTMS is a non-invasive brain stimulation technique that can be used to focally modulate activity in targeted brain regions. Studies have shown that multiple sessions of 1Hz inhibitory rTMS applied to the right hemisphere Pars Triangularis (PTr) of people with chronic aphasia results in improved naming abilities. These improvements accrue over time, and may persist even after rTMS has ended. It has been proposed that rTMS induces this improvement by reducing the disruptive influence of compensatory activity in the right hemisphere PTr, allowing for recruitment of more efficient left hemisphere peri-lesional brain areas. However, existing neuroimaging evidence to support this hypothesis is insufficient.

The goal of the proposed study is to investigate the neurological mechanisms underlying the effect of rTMS on naming performance in chronic aphasia. This will extend existing knowledge regarding hemispheric contributions to language recovery following stroke and elucidate how rTMS-induced neuroplasticity can be co-opted to encourage optimal reorganization. The study will also investigate a potential source of individual response variability to rTMS, one which can inform both candidate selection and optimal stimulation parameters. Sixteen participants will be enrolled, yielding a significantly larger sample size than previous studies that have examined changes in functional brain activation in response to rTMS (n = 1, 2).

All participants will receive a sequence of 1200 pulses of 1 Hz rTMS to right hemisphere PTr across 10 daily sessions. Half of the participants will also receive a 6 Hz rTMS excitatory priming pulse sequence immediately prior to the 1 Hz sequence. This priming sequence ensures a consistent inhibitory response to the subsequent 1Hz rTMS and will permit an examination of state-dependent individual response variability.

To evaluate the effect of rTMS over time, participants will undergo functional magnetic resonance (fMRI) scans at four time points: prior to initiation of rTMS ("baseline"), immediately following the first rTMS session ("post-rTMS"), following the conclusion of the rTMS series ("post-treatment") and at a 2-month follow-up visit. During the scans, participants will be asked to name pictures, and both patterns of regional naming-related activation and effective connectivity (directional causal influence between activated brain regions) will be evaluated at each time point. In addition, naming performance will be measured via standardized assessments at baseline, post-treatment, and follow-up.

Changes in naming performance will be assessed over time, as a measure of rTMS effectiveness overall and between groups (priming sequence vs no priming sequence). In addition, changes in activation and effective connectivity will be correlated with naming improvement to assess the relative effectiveness of right hemisphere recruitment compared to left hemisphere peri-lesional recruitment. Overall increases in left hemisphere recruitment are hypothesized to result in greater improvements. However, the magnitude of left hemisphere recruitment due to rTMS is expected to depend on baseline levels of right hemisphere PTr activity.

Results from this study will significantly improve the investigator's understanding of the effects of rTMS on stroke recovery. The results will also inform future studies evaluating rTMS as an adjunct to behavioral speech-language intervention, augmenting therapeutic gains from traditional aphasia treatment.

Inclusion Criteria:

• Aphasia due to unilateral left-hemisphere stroke

• Greater than 6 months post aphasia onset

• English as a first language

• No contraindications to MRI or TMS including:

  • pregnancy
  • presence of ferromagnetic substances in the head with the exception of dental fillings, stents or aneurysm clips documented to be MRI compatible
  • presence of any implanted devices including cardiac pacemaker, implanted cardiac defibrillator, insulin pump, cochlear implant, or drug infusion device
  • history of epilepsy; use of medications that are known to lower seizure threshold
  • severe claustrophobia

Exclusion Criteria:

• History for progressive neurological disease or premorbid language disorder
• Presence of severe motor speech disorder
• Drug or alcohol dependence, or significant mood or behavioral disorder that is not currently stable or medically managed

Approximately 3 months

An adverse event reporting form was completed at each assessment and treatment visit

Unable to collect all planned functional MRI data due to technical difficulties/scanner out of service.